Method and composition for controlling microorganisms containing tetrahydro-1,3,5-thiadiazine-2-thiones



EENQGE. SMBQH 300M l ilfwliiaii Fil -i r W United St nted Oct. 6, 1970 jury and destruction by microorganisms, also as disin- 3,532,793 fectant additives to cosmetic and hygienic compositions METHOD AND COMPOSITION FOR CONTROL- LING'MICROORGANISMS CONTAINING TETRA HYDRO-1,3,5-THIADIAZINE-2-THIONES Walter .Traber, Riehen, Switzerland, assignor to Geigy Chemical Corporation, New York, N.Y., a corporation of Delaware No Drawing. Original application Dec. 27, 1966, Ser. No.) 604,554, now Patent No. 3,497,506. Divided and this application Mar. 6, 1969, Ser; No. 829,821

Claims priority, application Switzerland, Dec. 29, 1965,

18,02 65 Int. Cl. A0111 9/12, 9/120, 13/00,- A61k 23/00 US. Cl. 424-246 8 Claims ABSTRACT OF THE DISCLOSURE Tetrahydro-l,3,S-thiadiaZine-Z-thiones of the formula wherein R and R independently of each other represent hydrogen, halogen or nitro, and R represents an unsubstituted aliphatic hydrocarbon radical or a hydrophilically substituted aliphatic hydrocarbon radical, which are useful as agents for controlling bacteria and fungi; composisuch as soaps and other cleansingagents.

Other aspects of the invention, therefore, provide for compositions for controlling microorganisms which comprise microbicidally effective amounts of a compound falling under Formula I and a carrier which is compatible with the latter and the use of such compositions for the protection of organic materials and articles of manufacture susceptible to the attack of microorganisms, especially bacteria andfungi, as well as for methods for such coiftroland protection for the aforesaid materials and articles of manufacture protected by effective amounts of a compound of Formula I or a composition containing the latter.

The unsubstituted or hydrophilically substituted aliphatic hydrocarbon radical R is, preferably, a lower alkyl or alkenyl radical such as methyl, ethyl, propyl, butyl, allyl or methallyl. As hydrophilic substituents R may contain, e.g. a hydroxyl or carboxyl group. The symbols R and R preferably represent halogen, particularly chlo-= rine or bromine, also a lower alkyl radical having from 1 to 4 carbon atoms.

The new tetrahydro-1,3,S-thiadiazine-Z-thiones according to the invention are produced by reacting a salt of a dithiocarbamic acid of-the general Formula II R tions containing them and organic materials and articles r of manufacture protected by these agents and composi- R2 s tions against attack by bacteria or fungi. S

SH (11) This application is a division of application Ser. No.

604,554, filed Dec. 27, 1966, now US. Pat. No. 3,497,506.

The present invention relates to new tetrahydro-1,3,5- thiadiazine-Z-thiones having valuable microbiggi al pr o p erties, processes for the production of these new compounds and also microbicidal compositions containing these tetrahydro-1,3,5-thiadiazine-2-thiones as active sub stances. It also relates to methods for controlling microorganisms and more especially fungi and bacteria, and for the pro tion oforganic materials and articles of manp;

facture from attack by microorganisms usifig sii dh ttrahydro-1,3,5-thiadiazine-2-thionesor compositions containing these compounds; and finally it relates to the materials and articles of manufacture protected by the novel com-= pounds against deterioration or destruction by fungi or bacteria.

In a first aspect the invention provides for the novel tetrahydro 1,3,5 thiadiazine-Z-thiones of the general Formula I wherein R and R independently of each other represent hydrogen, halOgen or nitro, and R represents an unsubstituted aliphatic hydrocarbon radical or an aliphatic hydrocarbon radical substituted by a hydrophilic group as defined hereinafter, which compounds possess valuable microbicidal properties; by these properties there is under stood a fungicide, bacteriostatic, fungistatic and in particular bactericidal activity. Their toxicity is slight. Thus, and because of their substantial colorlessness, the lack of irritant action on the human skin and mucous membranes, as well as because of their stability, particularly to heat and light, the new active substances can be used for the most varied purposes, e.g. for the protection of organic materials and articles of manufacture susceptible to in-= wherein R and R have the meanings given in Formula I, in any order desired with per mol thereof, two mols of formaldehyde and 1 mol of an amine of the general Formula III R NH (III) wherein R have the meaning given in Formula I, preferably however, with an addition salt of this amine with an inorganic or organic acid. As salts of dithiocarbamic acids of Formula II, the alkali or alkaline earth salts or salts of a tertiary amine are particularly suitable. The process described is preferably performed in the presence of a solvent which is inert to the reaction components and especially in water.

According to a variation of this process, salts of dithiocarbamic acid of Formula II are first converted into the free acid and this is then reacted with 2 equivalents of formaldehyde and 1 equivalent of an amine of general Formula III.

The salts of dithiocarbamic acid of general Formula II are produced by reacting a thenylamine of Formula IV R1 R I CH2NHz S amine, S-methyl 2 thenylamine, S-tert. butyl-Z-thenyh amine.

The following are examples of amines of general For mula III suitable in the above-described reaction with compounds of general Formula II: methylamine, ethylamine, I1 propylamine, isopropylamine, n butylamine, isobutylamine, sec. butylamine, tert. butylamine, allylamine, ethanolamine, propanolamine, ot-aminoacetic acid, fl-aminopropionic acid, -aminobutyric acid.

The amines of general Formula III are preferably used in the aforesaid reaction in the form of their salts, for instance, their hydrochlorides, sulphates, acetates, etc. The production of tetrahydro-1,3,S-thiadiazine-Z-thiones which are symmetrically or unsymmetrically substituted in the 3,5-position is known (cf. DAS 1,145,624, DAS 1,149,014, A. Rieche et al. Arch. Pharm. 296 (1963), pages 641 and 770). However, no unsymmetrically substituted tetrahydro 1,3,5 thiadiazine 2 thiones have hitherto been described which contain a five-membered heterocyclic radical bound to the 3-position on the thiadiazine-thione nucleus via an aliphatic bridging member, and which contain at the same time an aliphatic radical in the 5-position of the said nucleus.

It has now been found that in the agar incorporation test according to Leonard and Blackford J. Bact. 57, 339 (1949), which involves testing of the growth of bacteria and fungi on agar in which the active substances in various concentrations have been incorporated, the tetrahydro-l,3,S-thiadiazine-Z-thiones of general Formula I show an excellent growth-inhibiting action on microorganisms such. as bacteria, e.g. gram positive and gram negative bacteria, and fungi, e.g. Aspergillus nigcr, Penicillium ilalicum, Fusarium oxysporum, Candida albincans, Acrostalagmus spec., etc., so that they are par ticularly suitable for the protection of organic mate rials of all types from destruction and injury by such bacteria and fungi. Also, because of their low toxicitiy to mammals, the active substances can be used in hygiene and in cosmetics. In order to protect organic materials, the active substances of general Formula I are either incorporated into the material or the material is impregnated with a solution or dispersion of the protective ingredient. In this way, keratin materials such as skins, leather, wool, and also cellulosic materials such as wood, cellulose, paper, cotton, furthermore compositions such as glues, printing thickeners made from starch. and cellulose derivatives, oils of all types, processing liquors for paper and textiles, plastic and other synthetic materials of all types, can be protected from attack by such microorganisms.

For use in hygiene and as cosmetics, the active substances are incorporated into cleansing agents such as soaps and in cosmetics such as ointments, creams, deodor ants. Solutions for the impregnation of material are pre pared, particularly, with organic solvents such as petro= leum fractions, alcohols or ethers such as ethylene glycol alkyl ether. Surfactants suitable for the protection of material such as dispersing agents and other distributing agents can be added to these solutions whereby dispersions suitable for impregnation of material to be protected are obtained. Such solutions or dispersions have a content of active substance of at least 0.1 g./litre.

In all forms for application whether intended. for technical, cosmetic or hygienic purposes, the active sub-' stances of general Formula I can be used alone or to gether with other known microbicidal active substances.

They can be combined, for example, with halogenated salicyclic acid alkylamides and anilides, with halogenated diphenyl ureas, with halogenated beuzoxazoles or benz oxazolones, with polychlorohydroxydiphenyl methanes, with halogen-dihydroxydiphenyl sulphides, with halogen ated hydroxydiphenyl ethers, with 2-imino-imidazolidines or -tetrahydropyrimidines or with quaternary compounds or with certain dithiocarbamic acid derivatives such as tetramethyl thiuram disulphide. Optionally, carriers which themselves have a desirable microorganism-controlling action, such as sulphur or zinc stearate, can be used as a foundation for powders or as component of ointment foundations, respectively.

The following non-limitative examples illustrate the invention further. Where not otherwise stated, parts and percentages are given by weight. The temperatures are in degrees centigrade.

EXAMPLE 1 19.4 parts of aqueous formaldehyde solution (concentration about 36% by volume) are added to a solution of sodium N-thenyl-dithiocarbarnate produced from 34.4 parts of sodium carbonate, 36.6 parts of thenylamine and 24.6 parts of carbon disulphide, in 1300 parts of water. A small amount of oil which separates is filtered off, and 25.5 parts of ethylamine hydrochloride dissolved in 40 parts of water are added to the clear filtrate. The pH of the strongly alkaline solution is adjusted to 8-9 with concentrated hydrochloric acid and the solution is then stirred for 5 hours at room temperature (25). The crystalline substance which preciciptates is filtered off under suction, dried in vacuo and recrystallised from a mixture of benzine (B.P. -100) and benzene in a weight ratio of 1:2. The resulting 3-thenyl-5-ethyl-tetrahydro-1,3,S-thiadiazine-Z-thione melts at 131132.

In using corresponding amounts of the respective thenylamine, carbon disulphide and a base in the manner described in. Example I, the salts of the corresponding dithiocarbamic acid of general Formula II are produced and these salts are then reacted with formaldehyde and the hydrochloride of the corresponding amine of general Formula III to form the new tetrahydro-l,3,5-thiadiazine- J2-thiones listed below.

th adiazine-Z-thione. M- 3-(5-methylthenyl)-5-allyl-tetrahydr0-1,3,5-thiadiazine-2 thione. 3-(5' -ethylthenyl)-5-carboxypropoyl-tetrahydro- 1,3,5-thiadiazine-2-thione.

The antimicrobial action of the compounds according to the invention was determined by the following test series, the degree of effectiveness of the tested compounds being given in the following table.

The antimicrobial action of some of the compounds according to the invention was tested in the following test programme, the effectiveness of the tested compounds being given in the following table:

1) The bactericidal action was tested on the following strains of bacteria: Staphylococcus aurous SG 511, Escherichia coli NCTC 8196, Bacillus pumilus, Sarcina ureae, Pseudomonas pyocyanea.

The test method was the Agar incorporation test ac cording to Leonard and Blackford: Nutrient agar plates with 100, 30, 10 and. 3 ppm. of active substance (p.p.m. means parts of active substance per 10 parts diluent) were inoculated with solutions of the above strains and then incubated for 2 times 24 hours at 37 The following table shows the minimum concentrations which inhibit the growth of the individual strains:

usual way and dried. On being tested, the wool is found to be resistant to attack by bacteria and fungi.

(2) The fungicidal action was tested on the following strains of fungi: Aspergillus niger, Penicil'lium italic-um, Fusarium oxysporum, Candida albz'cans, Acrostalagmus EXAMPLE 17 The following process, for example, can be used for the application of 3-theny1- 5 (2 hydroxyethyl)-tetra spec.

The Agar incorporation test according to Leonard hydro-1,3,5-thifldiaZiho-2-thiohe1 and Blackford was used as test method. Nutrient agar 0.5 pa t of active ihgredioht are dissolved in 10 P21rts mates i h 100, 30, 10 d 3 of active substance of dimethyl formamide and the solution is poured into were inoculated with solutions of the above strains and 3000 Parts of Water Which contains about Parts of incubated for 3 times 24 hours at 28. The minimum conall emulsifying agent, Sulfohated Castor centrations which inhibit the growth of the individual 100 parts of Wool are treated in this liquor for 30 minstrains are given in the following table: utes at the boil. After rinsing and drying, the wool is Pen. Fus. Cand. Asp. italiorg albi- Acto Compound niger cum sporu'm cans spec.

3-thenyl-5-carboxymethyltetrahydrol,3,5-thiadiazine-2-thione 100 10 100 100 10 3-(5-ehlorothenyl)-5-(2-hydroxyethyl)- tetrahydro-l,3,5-thiadiazine-2-thione 100 30 100 30 30 3-(5-chlorothenyl)-5-isopropyl-tetrahydro-l,3,5-thiadiazine-2-thione 100 10 30 30 100 The following non-limitative examples describe the profound to be resistant to attack by bacteria and fungi. duction of various forms suitable for application in prac- The treatment baths in Examples III and IV may also tice. The parts and percentages are given therein by contain other auxiliaries as well as dyestuffs. Weight EXAMPLE 14 EXAMPLE 18 First a 20% solution of 3-(5'-chloroethyl)-5-iso-propyl- I g 0 ide is prepared. 10 parts by volume of this solution are diparts of dlmethyl formamlde and 50 parts of .ethylqne 40 luted with 200 parts by volume of a solvent suitable for glycol l9 l h .5000 parts of a dlipcr S1011 dry cleaning e.g. a suitable benzine fraction (Diluan S). 9 wmammg a White Plgment i copolymenc y If desired, cleansing additives can be added. Woolen arvmyl acetate base as and havmg about 50% Sohd ticles are then treated in this cleaning liquid in the usual coiltent are adfied to P soluilon' The readyffor'use way and then squeezed out to a content of solvent of paint thus obtamed, which contains 0.1% of active sub-= about 100% of the Weight of the W001 After drying, Stance 13 Proof agamst attack by bactena" they are found to be resistant to attack by bacteria and EXAMPLE 15 :fungii r I c aim: g 15 produced by mlxmg the fouoWmg compo A composition for controlling bacteria and fungi Parts Which comprises a bactericidally and funglcidally effective Tallow soap- 76 76.5 amount of a compound of the formula Active substance, e.g. 3-thenyl-5-(2-hydroxy=- R1 ethyl)-tetrahydro-I,3,5-thiadiazine-2-thione 0.5-1 Coconut oil soap or palm oil soap 11 15.000 R j I I Free alkali (calculated as Na O) 0.010 fi J CH2 N-Ra Water 6.065 s V gi gg fiflggg t wherein R and R independently of each other repre- Dyestuff N 0050 sent hydrogen, halogen or mm, and R represents alkyl Titanium White 0.125 having 1 to 4 carbon atoms, alkenyl having 3 or 4 carbon sequestrene ST (Sodium ethylenedl-amine tetra atomsor hydrophilically substituted alkyl wherein the hy= acetate) N 0050 drophilrc groups are hydroxyl or carboxyl and an inert Glycerol 0.500 carrier for said compound.

a 2a A composition as defined in claim 1, wherein said The feslllhng Soap has mlolohloldal W active ingredient is 3-thenyl 5 methyl-tetrahydro-l,3,5-

EXAMPLE 1 thiadiazine-Z-thione.

3., A composition as defined in claim 1, wherein said par of y s'lsoPropyl'tetl'ahyfiro'1,35'th1ad1" active ingredient is 3-thenyl 5 (2-hydroxyethyl)-tetraaz1ne-2-th1one are drssolved 1n 5 parts of dimethylsulphoxhydro13,5 thiadiazine z thione 1de and a little ethanol. This solution 1s diluted with 3000 A composition as defined in claim 1, wherein said Parts Water which oohtfllhs about 2 Parts of Turklsh active ingredient is 3-thenyl-5-carboxymethyl-tetrahydro red 011 as emulsifier, and parts of wool slubbing are 1,3,S-thiadiazine-Z-thione. treated in this liquor for 15 minutes at 60 5 parts of 5. A composition as defined in claim 1, wherein said 10% acetic acid are added and the treatment at 60 is active ingredient is 3-(5'-chlorothenyl)-5-(2"-hydroxy= '2' 5 ethyl) -tetrahydro- 1,3 ,5 -thiadiazine-2-thione.

continued for another hour The wool is then rinsed in the 7 6. A composition as defined in claim 1, wherein said active ingredient is 3-(5'-ch1orothenyl)=5-isopropyltetrahydro-1,3,S-thiadiazine-Z-thione.

7. A method tor controlling bacteria and fungi applyin: to said bacteria and fungi a baeterieidaily and fungi- 6 cidally effective amount at a tetrahydro=1,3,5=thiadiazine 7-thione as defined in claim 1.

I. A method ior controlling bacteria and fungi which comprises applying to said bacteria and fungi a bacterial as defined in claim 1.

' 8 References Cited UNITED STATES PATENTS 3,277,082 10/1966 Benjamin 424-246 XR 3,277,087 10/1966 Fei et a1. 424-246 XR ALBERT T. MEIERS, Primary Examiner D. R. ORE, Assistant Examiner US, Cl. X3.

daly and iungieidally effective amount of a composition 3 1 5; 117=1as.s,14z,14a, 141, 154; zs2=s.s7, 3.3,

US 2318 DIV A November 10, 1970 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Dated October 6, l9'ZO Patent No.

Invented Walter Traber It is certified that error appear and that said Letters Patent are hereby correct s in the above-identified patent ed as shown below:

Column 7, line 4: after fungi, add --which comprises--.

S Am

Edward M. Fletcher, Ir.

[meaning Officer Gomiasiomr 0 Pa ants USCOMM-DC 603764 09 e u s sovimmnn nmmm; orract nu 0-3-33l F ORM PO-IOSD (10-69) 

